Type 1 interferon-(alpha, beta, omega)-producing cells (IPC/pDC), or plasmacytoid dendritic cell precursors (pDC) represent 0.2-0.8 of peripheral blood mononuclear cells in both humans and mice. IPC/pDC display plasmacell morphology, have the capacity to produce a large amount of type 1 IFN following viral stimulation, and are able to differentiate into professional antigen presenting dendritic cells (called plasmacytoid DCs). Studies of HIV-infected human subjects and of a murine model of viral infection demonstrated that IPC/pDC are the key effectors in anti-viral innate immunity. In addition, recent studies have shown that patients suffering from systemic lupus erythematosis (SLE) have an elevated level of serum IFN-a, resulting from constitutively activation of IPC/pDC by DNA and anti-DNA antibody complexes in SLE patients, and contribute to the pathological processes of SLE. Therefore understanding the developmental regulation of IPC/pDCs may have important implication in controlling viral infections and autoimmune diseases. We have previously shown that FLT3-L represents a key differentiation factor for IPC/pDC development from hematopoietic stem cells in humans and mice, and developed the in vitro culture system to generate human and mouse IPC/pDC. However, the developmental steps of IPC/pDC from early hematopoietic stem cells, and its lineage relationship to lymphoid and myeloid lineages are poorly defined. The molecular regulation of IPC/Pdc development by other growth factors and signaling pathways are largely undefined. In this grant application, we have three aims: 1) To define the developmental steps and lineage origin of human IPCs; 2) to define the developmental steps and lineage origin of mouse IPCs; and 3) to investigate the molecular mechanisms which regulate IPC development.